Incidence rates of non-Hodgkin lymphoma (NHL) have increased dramatically in the U.S. and other industrialized countries over the past 40 years, though reasons for this rise in rates are largely unexplained. In 2005, it has been estimated that NHL will account for 56,390 newly diagnosed cases and 19,200 associated deaths. Family and population-based studies provide evidence that genetic susceptibility plays a role in lymphomagenesis. However, the contribution of common genetic alleles and gene-environment interactions needs further investigation. Using Perlegen high-density oligonucleotide arrays, genome-wide genotyping on pooled DNA will be conducted to screen for NHL susceptibility markers. 267,000 haplotype tagging single nucleotide polymorphisms (SNPs) will be evaluated that span the genome on DNA pools from 1,000 NHL cases and 1,000 controls in a large population-based case-control study in the San Francisco Bay Area (recruitment of 2,000 cases and 2,000 controls to be completed in Spring 2006). Over 1,400 cases and 1,400 controls already have been ascertained with extensive epidemiological information collected from all study participants. Once target genes are identified by pooled genotyping, the association of these loci with NHL risk will be verified and further investigated by individual genotyping. An additional 7,000 SNPs will be individually genotyped in the human leukocyte antigen (HLA) region to investigate the involvement of HLA loci in the pathogenesis of NHL. Positive findings will be replicated in a second set of 1,000 NHL cases and 1,000 controls. Fine mapping genotyping will be performed on confirmed genes of interest. To add an additional replication step, another approximately 400 NHL cases and 800 controls from a previous NHL study (based in the San Francisco Bay Area) will be genotyped. This study, which constitutes one of the largest case-control NHL genetic epidemiology studies conducted to date, will broaden our current understanding of important mechanistic pathways involved in lymphomagenesis. Furthermore, these results may be translated to NHL screening, prevention or treatment regimens. The data generated from this study will provide a framework for further investigation within the NHL consortium, InterLymph. Results will later be combined with that from other InterLymph case-control studies in pooled analyses.